Method and device for coating pharmaceutical products

ABSTRACT

The present invention relates to a method for coating of a pharmaceutical product. The method comprises the step of producing discrete droplets ( 7 ) of controlled size, shape and composition with at least one micro dispenser ( 1 ) and distributing droplets ( 7 ) with controlled velocity, time of flight. Also, the method comprises the step of controlling the production frequency and modulation of the droplets ( 7 ). Further, the method comprises the step of controlling the flow rate, temperature and composition of the carrier gas and directing droplets ( 7 ) towards particles ( 10 ) subjected to coating. The present invention also relates to a device for coating of a pharmaceutical product. The device comprises a droplet producing unit ( 1 ) and a droplet-directing unit ( 8 ). The droplet producing unit ( 1 ) is a piezo-actuated micro dispenser ( 1 ) for producing discrete droplets ( 7 ) and controlling the size, shape and composition of said droplets ( 7 ).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national phase application under 35 U.S.C. § 371of PCT International Application No. PCT/GB02/03143, which has anInternational filing date of Jul. 9, 2002, and which designated SwedishApplication Serial No. 0102511-3, filed Jul. 12, 2001, as priority. Thecontents of these applications are incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to a method and device for coating of apharmaceutical product. Essentially, the invention relates to producingcoating droplets of controlled size, shape and composition and withcontrolled velocity.

BACKGROUND OF THE INVENTION

The production of pharmaceutical solid dosage forms involves amultistage operation. It requires between six and eight unit processes,such as charging of raw materials, milling, granulation, drying,blending, compression, coating and packaging. Generally, a coating of apharmaceutical product consists of one or more films and each filmconsists of one or more layers. From here and on “coating” is used as acomprehensive expression encompassing everything from an individuallayer to a combination of several different films. Each film is theresult of a single coating step, generally carried out in a coatingvessel where, for instance, layers of the film are built up. The coatingprocess takes place either in a fluidised bed wherein particles,so-called nuclei, are sprayed with a specific coating liquid, or bypassing the particles through a spray dust of said liquid. Several othergenerally used coating techniques are known in the prior art, such asmelting, aggregation etc. The total process of manufacturing a completecoating may involve a plurality of such coating steps. However, theprocess may as well be sequential, whereby the whole process representsa continuous flow.

Pharmaceutical products are coated for several reasons. A protectivecoating normally protects the active ingredients from possible negativeinfluences from the environment, such as for example light and moisturebut also temperature and vibrations. By applying such a coating, theactive substance is protected during storage and transport. A coatingcould also be applied to make the product easier to swallow, to provideit with a pleasant taste or for identification of the product. Further,coatings are applied which perform a pharmaceutical function such asconferring enteric and/or controlled release. The purpose of functionalcoating is to provide a pharmaceutical preparation or formulation withdesired properties to enable the transport of the active pharmaceuticalsubstance through the digestive system to the region where it is to bereleased and/or absorbed. A desired concentration profile over time ofthe active substance in the body may be obtained by such a controlledcourse of release. An enteric coating is used to protect the productfrom disintegration in the acid environment of the stomach. Moreover, itis important that the desired functionalities are constant over time,i.e., during storage. By controlling the quality of the coating, thedesired functionalities of the final product may also be controlled.

There are strict requirements on pharmaceutical products. Theserequirements will put high demands on the quality of the coating andrequire that the complex properties of the coating will be kept withinnarrow limits. In order to meet these demands, there is need foraccurate control of the coating process.

The quality of the coating depends on physical and/or chemicalproperties of the coating, such as chemical composition, localinhomogeneities, physical and chemical homogeneity, density, mechanicalproperties, static parameters, modulus, tensile strength, elongation atbreak, compression, ductility, viscoelastic parameters, morphology,macro- and microscopic properties, amorphous and/or crystallinity,permeability, porosity, aggregation, wettability, degree ofcoalescence/maturity, stability and ability to resist chemical and/orphysical degradation. There are also other properties not listed above.The quality of the coating affects to a great extent the releaseproperties and has a significant impact on the storage stability. Inorder to keep the quality of the coating within the desired narrowlimits it is necessary to control the manufacturing process of thecoating accurately.

In an industrial plant for coating pharmaceutical products, selectedprocess parameters are monitored and controlled to achieve a desiredquality of the end product. Such process parameters are generally globaland could include, for example, the pressure in the coating vessel, theflow rate and temperature of gas and coating liquid supplied to thecoating vessel, etc. However, the influence of such global processparameters on the coating process, and ultimately on the coatingproperties of the end product, is known only from experience in aspecific plant. Thus, a processing scheme is developed for each specificplant by extensive testing. When, for example, the size or shape of thecoating vessel is changed during scaling up of the process the localenvironment of the particle may be altered. This calls fortime-consuming measurements and adjustments in order to regain the samecoating properties of the end product.

There is also a need to improve existing-manufacturing processes as wellas to improve existing plants. Today, this is a laborious task since theinfluence of any change in the process scheme or the plant design on theend product has to be investigated by extensive testing, often in fullscale. The same applies to the development of new products, for examplewhen a new type of particle or coating liquid should be used.

An attempt to fulfil the above-identified needs is disclosed in thearticle “Fluidized bed spray granulation, investigation of the coatingprocess on a single sphere” by K. C. Link and E. U. Schlünder, publishedin Chemical Engineering and Processing, No. 36, 1997. A laboratory-scaleapparatus is designed for analysis of a single particle in order toinvestigate the fundamental physical mechanisms that lead to particlegrowth by layering. In this apparatus, a single aluminium sphere is madeto levitate on a fluidising airflow, which is supplied by a capillarytube. Thereby, the sphere is freely and rotatably suspended at a stablelocation in a coating vessel. An ultrasonic nozzle arranged above thisstable location is intermittently activated to generate a spray dust ofcoating liquid that falls down onto the sphere and forms a coatingthereon. This type of nozzle generates a spray of droplets, the velocityof which is adjusted by means of a separate airflow through the nozzle.The apparatus is used for investigating the influence of differentparameters, such as droplet velocity, temperature of fluidising air,drying time, and type of coating liquid, on the thickness and morphologyof the resulting coating. A rough measurement value of the overallthickness of the coating is obtained by weighing the sphere before andafter the actual coating process and determining the difference inweight. The morphology of the coating is qualitatively examined byarranging the sphere, once coated, in a scanning-electron-microscope(SEM). For both these measurements, the sphere must be removed from theapparatus for analysis. The apparatus also includes a lamp forillumination of the sphere and a video camera for continuous andqualitative observation of the contours of the sphere during the coatingprocess. One drawback of this prior art apparatus resides in thedifficulty to make quantitative, time-resolved measurements of coatingproperties. After a specific time period, the coating process must beinterrupted for analysis of the coating on the sphere, whereupon a newand non-coated sphere must be subjected to a new coating process for alonger time period, and so on. In this approach, the formation of acoherent time series of measurement data requires that identicalconditions be maintained in the environment of each sphere. Thus, thecoating process must be repeated in exactly the same manner for eachsphere. This is difficult. For example, any small variation in themasses of the aluminium spheres will necessitate an adjustment in theflow rate of the fluidising air to maintain each sphere at the samelocation in the vessel. Such a change in flow rate will also change theenvironment of the sphere during the coating process, thereby making itdifficult to compile the measurement data from several consecutivemeasurements into coherent time series.

A further drawback of this known apparatus is that only a few propertiesof the coating, i.e. average thickness and surface morphology, can bemeasured.

Another drawback is that the course of coating process can only bestudied on standardised spheres, so that the coating process can berepeated in exactly the same manner for each sphere. However, thecoating process is believed to be highly dependent on the properties ofthe particle itself, such as the size, density, porosity and shape ofthe particle. Thus, it may be difficult, or even impossible, to draw anyconclusions for a realistic particle from experiments made in the knownapparatus.

In a paper by S. Watano and K. Miyanami, “Control of Granulation Processby Fuzzy Logic”, North American Fuzzy Information, 1999, 18^(th)International Conference of the NAFIPS, pp 905-908, a system forgranulation is described. A system has been developed for on-linemonitoring of granule growth in fluidised bed granulation utilising bedgranulation. However, since an image analysis is carried out the dataavailable is limited to size and shape.

The papers above describe systems for monitoring the coating andgranulation, respectively. However, the production of droplets isrelatively rough and the repeatability of droplet size, velocity anddirection is inadequate. Also, in a coating process it is desirable thatthe droplets produced hit and impinge the particles subjected tocoating.

A paper by T. Laurell et al., “Design and development of a siliconmicrofabricated flow-through dispenser for on-line picoliter samplehandling”, Journal of Micromechanical Microengineering, No. 9, 1999, pp369-376, discloses a method for producing droplets with highrepeatability as regards size. However, at a coating process in forexample a fluidised bed, the gas/air in the vessel is circulated andthereby carries the droplets that, if the process is properly adjusted,hit the particles subjected to coating. A major drawback is that thedroplets have approximately the same velocity as the particles subjectedto coating and the time of flight for the droplets are therefore oftento long. This results in the droplets drying and very often not at allimpinging on the particles subjected to coating. Generally the dropletsconsists of substances that are costly and therefore it is desirable tokeep production loss down.

SUMMARY OF THE INVENTION

The object of the present invention is to solve or alleviate some or allof the problems described above. This object is achieved with a methodand a device according to claim 1 and claim 15, respectively. Preferredembodiments of the invention are given by the depending claims.

Thus, the method according to the invention for coating of apharmaceutical product, comprises the steps of producing discretedroplets of controlled size, shape and composition with a microdispenser, controlling the production frequency and modulation of thedroplets, distributing droplets with controlled velocity and time offlight, controlling the flow rate, temperature and composition of thecarrier gas, and directing droplets towards particles subjected tocoating. The inventive method will allow for production of droplets ofcontrolled size, shape and composition and not dependent on the airflowin, for example, a vessel for a fluidised bed. Normally in a fluidisedbed, the particles to be subjected to coating are circulated in thevessel by a jet stream, said jet stream also shattering a coating liquidand thereby producing droplets. If the system is well tuned the dropletshit the particles immediately after they leave the jet nozzle. However,since the flow circulating the particles in the vessel are directlydependent on the flow in the jet stream, the scale up from test rigs torunning production units are very laborious and very often fail. Withthe inventive method the release of droplets is carried out independentof said flow. By using a separate gas flow to accelerate the dropletsthe velocity can also be determined independent of the flow inside, forexample, a vessel or a pipe. This separate gas flow or carrier gas canbe controlled as regards flow rate, temperature and composition.Further, the production frequency and modulation of droplets arecontrolled in order to increase the coating quality.

By controlling the flow rate of the carrier gas the velocity of thedroplets can be controlled to be higher than the flow in the vessel orpipe. Being able to control the temperature and composition of thecarrier gas can facilitate the coating using specific coatingsubstances, i.e. avoiding for example chemical reactions and drying outof the substance. Also, by directing the droplets the loss of coatingsubstance can be kept at a minimum.

The production of droplets is preferably carried out utilising apiezo-actuated micro dispenser. The piezo-actuated micro dispenser hasthe advantages of a relatively simple construction, and therebyeconomically beneficial, and very low standard deviations in size, shapeand composition of the droplets.

As previously mentioned a separate gas can be used to carry thedroplets. To further improve the accuracy of aim of the droplets ahollow cone is preferably used, or a device with corresponding flowprofile, which enhance the controllability of the direction of thedroplets. Due to the flow field in the cone the droplets will be forcedto enter the capillary in the top of the cone. The shape of the velocityprofile in the gas stream inside the capillary contributes to forcedroplets from impinging the wall of the capillary (Saffman force). Bychanging the flow rate of the carrier gas the velocity of the dropletswhen they impinge on the particles subjected to coating can be variedand hence the momentum of the droplets when they impinge on theparticles subjected to coating can be varied. Common problems in coatingin prior art is the occurrence of drying before the droplets impinge onthe particles subjected to coating and not being able to direct thedroplets towards the particles, which leads to a decrease in coatingefficiency and also a non-optimal coating situation. By controlling thetemperature and composition of the carrier gas, the drying rate of thedroplets can be held at a minimum level.

Preferably, the micro dispenser is mounted in the centre of the base ofsaid hollow cone. Due to the flow field in the cone the droplets will beforced to enter the capillary in the top of the cone.

The coating method is preferably utilised in a fluidised bed or forcontinuous coating in a pipe/tube, whereby several “cones” comprisingmicro dispensers are positioned in or adjacent to the bed or thepipe/tube. However, it is possible to utilise the method according tothe present invention with coating techniques such as in a fluidised bedwith top spray, with a rotor tangential spray coater and in a coatingpan.

In order improve the result of the coating the coating and dropletproduction is preferably monitored. The monitoring can be carried outperforming spectrometric measurements and preferably continuous. Thespectrometric measurement can be performed by means of a spectrometricmethod based on any part of the electromagnetic spectrum. Anotherpossibility is to perform the spectrometric measurement by means ofimaging spectrometry. If the monitoring is carried out continuously, theoutput from these measurements can be used as input signals to thedroplet production unit and thereby maximise the efficiency of thecoating.

A device for coating of a pharmaceutical product according to thepresent invention comprises a piezo-actuated micro dispenser as dropletproducing unit in order to produce droplets with controlled size, shapeand composition. The droplet-directing unit comprises a hollow cone inwhich a carrier gas is made to flow and to transport the dropletsproduced by the micro dispenser.

Several devices such as said device could be arranged in one-, two- orthree-dimensional arrays, wherein each of the devices is separatelycontrolled. Such multiple unit systems could be used in order to havedifferent coating zones in for example a fluidised bed coating processor in a continuous coating process where several coating zones can bearranged along the flow path of the particles.

BRIEF DESCRIPTION OF DRAWINGS

The above and other features and advantages of the invention are definedin the claims and described in greater detail below with reference tothe accompanying drawings, which illustrate preferred embodiments.

FIG. 1 is a cross-sectional view of a piezo-actuated micro dispenseraccording to the present invention.

FIG. 2 is a cross-sectional view of a piezo-actuated micro dispenserwith droplet substance according to the present invention.

FIG. 3 is a side view of a micro dispenser and a hollow cone accordingto the present invention.

FIG. 4 shows some steps in the production of a coated article forpharmaceutical products.

FIG. 5 shows an array of droplet directing units arranged adjacent apipe.

DESCRIPTION OF PREFERRED EMBODIMENTS

The micro-dispenser 1 in FIG. 1 according to the present inventioncomprises a first silicone structure 2 with an orifice joined togetherwith a second silicone structure 3. The two silicone structures 2 and 3form a flow-through channel for a substance 6 (shown in FIG. 2) to beused as a coating for the particles. In a preferred embodiment of thepresent invention the two silicone structures, 2 and 3, rest uponPlexiglas® stands 4. The micro-dispenser 1 is actuated through apiezo-ceramic plate 5. The generation of the pressure wave is lessefficient when attaching the piezo-ceramic plate directly to thesilicone structure 3 than when mounting the piezo-ceramic plate 5 onPlexiglas® stands 4.

FIG. 2 illustrates the micro-dispenser 1 when actuated by thepiezo-ceramic plate 5. The second said silicone structure 3 is bentinwards as a result of the voltage applied on the piezo-ceramic plate 5.As a result thereby a droplet 7 of coating substance 6 is produced andsqueezed out through the orifice in said first silicone structure 2.

The micro-dispenser 1 is in a preferred embodiment of the presentinvention arranged in the centre of the base of a hollow cone 8, whichis illustrated in FIG. 3. A carrier gas is supplied around themicro-dispenser in an upward direction in order to carry the droplets 7.By changing the flow rate of the carrier gas the velocity of thedroplets 7 can be varied. Due to the flow field in the hollow cone 8 thedroplets will be forced to enter the capillary in the top of the cone.Due to the velocity profile inside the capillary the Saffman forceprevents the droplets 7 from impinging the wall of the capillary. Thecarrier gas is preferably adapted to the substance of the droplets 7. Bycontrolling the temperature and composition of the carrier gas, thedrying rate can be adjusted to create optimal drying conditions for acertain coating quality.

Referring to FIG. 4, the coating device shown in FIG. 3 is preferablyarranged in a fluidised vessel 9. Particles 10 subjected to coating aremade to flow in the fluidised vessel 9, for example using a jet nozzle(the coating device and jet nozzle are not shown in FIG. 4).

In a preferred embodiment of the present invention several devices (notshown in FIG. 4) similar to the one shown in FIG. 3 are arranged in thevessel 9. By arranging monitoring equipment (not shown) the coatinglayers of the particles 10 subjected to coating as well as the dropletgeneration can be analysed and an algorithm decides when the microdispensers 1 are to produce droplets and their properties. Also, saiddevices are positioned as desired according to the results of themonitoring.

In a further preferred embodiment of the present invention severaldevices similar to the one shown in FIG. 3 are arranged to coatparticles continuously in a pipe/tube. Also with this arrangement it ispossible to monitor the coating and thereby achieve information in orderto maximise the quality of the coating.

The supply of carrier gas in the device shown in FIG. 3 is preferablyindependent of the gas flow inside the vessel 9. One advantage with thisis that the droplets 7 can be accelerated to have a higher velocity thanthe particles 10 subjected to coating in the vessel. This will in turnincrease the fraction of droplets 7 hitting the particles 10 subjectedto coating. When the coating is completed the pharmaceutical particles10 can for example be put in capsules II or mixed with filler andcompressed to tablets 12.

FIG. 5 shows a continuous coating process according to the presentinvention. Particles 10 subjected to coating are transported in apipe/tube 13, said pipe/tube 13 being equipped with coating devices 8.The coating devices 8 are arranged in several arrays 14, 15, each of thearrays correspond to one layer of coating. The arrangement of thecoating devices 8, such as angles, spacing and number, within the arrays14, 15 are varied to maximise the coating quality.

The foregoing is a disclosure of preferred embodiments for practisingthe present invention. However, it is apparent that device and methodincorporating modifications and variations will be obvious to oneskilled in the art. Inasmuch as the foregoing disclosure is intended toenable one skilled in the art to practice the instant invention, itshould not be construed to be limited thereby, but should be construedto include such modifications and variations as fall within its truespirit and scope.

1. A method of coating particles of a pharmaceutical product inside avessel or a pipe, comprising the following steps: producing discretedroplets with at least one micro dispenser; controlling the flow rate,temperature and composition of a carrier gas flowing from a supply to adroplet directing unit; causing the particles to flow in the vessel orpipe; using the carrier gas, directing droplets through the dropletdirecting unit towards the particles in the vessel or pipe; and coatingthe particles with the droplets; wherein the supply of the carrier gasis independent of the flow of particles inside the vessel or pipe suchthat the droplets are accelerated to have a higher velocity than theparticles.
 2. A method as set forth in claim 1, wherein the productionof the discrete droplets is carried out using a piezo-actuated microdispenser.
 3. A method as set forth in claim 1, wherein the droplets areaccelerated by the carrier gas.
 4. A method as set forth in claim 1,further comprising adjusting the velocity of the droplets by varying theflow rate of the carrier gas.
 5. A method as set forth in claim 1,wherein die droplet directing unit comprises a hollow cone.
 6. A methodas set forth in claim 5, wherein the hollow cone surrounds the microdispenser.
 7. A method as set forth in claim 1, wherein the coating isperformed in a fluidised bed.
 8. A method as set forth in claim 1,wherein the coating is performed continuously in a pipe, in which saidpharmaceutical product is transported by a carrier gas.
 9. A method asset forth in claim 7, wherein the formation of the coated pharmaceuticalproduct is monitored.
 10. A method as set forth in claim 9, wherein themonitoring is carried out performing spectrometric measurement.
 11. Amethod as set forth in claim 10, wherein said spectrometric measurementis carried out continuously.
 12. A method as set forth in claim 10,wherein said spectrometric measurement is performed by means ofspectrometric method based on any part of the electromagnetic spectrum.13. A method as set forth in claim 10, wherein said spectrometricmeasurement is performed by means of imaging spectrometry.
 14. A methodas set forth in claim 9, wherein the output from said monitoring is usedas input to control the distribution of the droplets.
 15. A device forcoating particles of a pharmaceutical product inside a vessel or a pipein which the particles flow, the device comprising a droplet producingunit, a droplet directing unit, the droplet producing unit comprising apiezo-actuated micro dispenser configured to produce discrete droplets,and a supply of a carrier gas provided for transporting droplets throughsaid droplet-directing unit to coat said particles, the supply ofcarrier gas being independent of the flow of particles inside the vesselor pipe such that the droplets are accelerated to have a higher velocitythan the particles.
 16. A device as set forth in claim 15, wherein thepiezo-actuated micro dispenser comprises a piezo-ceramic element.
 17. Adevice as set forth in claim 15, wherein the micro-dispenser comprisestwo joined silicone structures forming a flow-through channel.
 18. Adevice as set forth in claim 16, wherein stands are provided betweensaid micro dispenser and said piezo-ceramic element, spacing the microdispenser from the piezo-ceramic element.
 19. A device as set forth inclaim 17, wherein said flow-through channel comprises an orifice.
 20. Adevice as set forth in claim 15, wherein the device comprises an arrayof droplet producing units and droplet directing units.
 21. A device asset forth in claim 20, wherein each droplet producing unit is separatelycontrolled.
 22. A device as set forth in claim 20, wherein severalarrays are arranged in a coating device selected from the groupconsisting of fluidized beds, fluidized vessels, pipes, tubes, fluidizedbeds with a top spray, rotor tangential spray coaters, and coating pansto provide different coating zones in the coating device.
 23. A deviceas set forth in claim 22, wherein the coating device comprises afluidised bed.
 24. A device as set forth in claim 22, further comprisinga pipe or tube configured for continuous coating.